Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases
Standard
Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases. / Song, Feizhi; Kovac, Valerija; Mohammadi, Behnam; Littau, Jessica L; Scharfenberg, Franka; Matamoros Angles, Andreu; Vanni, Ilaria; Shafiq, Mohsin; Orge, Leonor; Galliciotti, Giovanna; Djakkani, Salma; Linsenmeier, Luise; Černilec, Maja; Hartman, Katrina; Jung, Sebastian; Tatzelt, Jörg; Neumann, Julia E; Damme, Markus; Tschirner, Sarah K; Lichtenthaler, Stefan F; Ricklefs, Franz L; Sauvigny, Thomas; Schmitz, Matthias; Zerr, Inga; Puig, Berta; Tolosa, Eva; Ferrer, Isidro; Magnus, Tim; Rupnik, Marjan S; Sepulveda-Falla, Diego; Matschke, Jakob; Šmid, Lojze M; Bresjanac, Mara; Andreoletti, Olivier; Krasemann, Susanne; Foliaki, Simote T; Nonno, Romolo; Becker-Pauly, Christoph; Monzo, Cecile; Crozet, Carole; Haigh, Cathryn L; Glatzel, Markus; Curin Serbec, Vladka; Altmeppen, Hermann C.
in: ACTA NEUROPATHOL, Jahrgang 148, Nr. 1, 09.07.2024, S. 2.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases
AU - Song, Feizhi
AU - Kovac, Valerija
AU - Mohammadi, Behnam
AU - Littau, Jessica L
AU - Scharfenberg, Franka
AU - Matamoros Angles, Andreu
AU - Vanni, Ilaria
AU - Shafiq, Mohsin
AU - Orge, Leonor
AU - Galliciotti, Giovanna
AU - Djakkani, Salma
AU - Linsenmeier, Luise
AU - Černilec, Maja
AU - Hartman, Katrina
AU - Jung, Sebastian
AU - Tatzelt, Jörg
AU - Neumann, Julia E
AU - Damme, Markus
AU - Tschirner, Sarah K
AU - Lichtenthaler, Stefan F
AU - Ricklefs, Franz L
AU - Sauvigny, Thomas
AU - Schmitz, Matthias
AU - Zerr, Inga
AU - Puig, Berta
AU - Tolosa, Eva
AU - Ferrer, Isidro
AU - Magnus, Tim
AU - Rupnik, Marjan S
AU - Sepulveda-Falla, Diego
AU - Matschke, Jakob
AU - Šmid, Lojze M
AU - Bresjanac, Mara
AU - Andreoletti, Olivier
AU - Krasemann, Susanne
AU - Foliaki, Simote T
AU - Nonno, Romolo
AU - Becker-Pauly, Christoph
AU - Monzo, Cecile
AU - Crozet, Carole
AU - Haigh, Cathryn L
AU - Glatzel, Markus
AU - Curin Serbec, Vladka
AU - Altmeppen, Hermann C
N1 - © 2024. The Author(s).
PY - 2024/7/9
Y1 - 2024/7/9
N2 - Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
AB - Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
KW - Humans
KW - ADAM10 Protein/metabolism
KW - Neurodegenerative Diseases/metabolism
KW - Amyloid Precursor Protein Secretases/metabolism
KW - Animals
KW - Prion Proteins/metabolism
KW - Membrane Proteins/metabolism
KW - Brain/metabolism
KW - Antibodies
U2 - 10.1007/s00401-024-02763-5
DO - 10.1007/s00401-024-02763-5
M3 - SCORING: Journal article
C2 - 38980441
VL - 148
SP - 2
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 1
ER -